The Rectal Microbicide Research Agenda Ian McGowan MD PhD FRCP Magee Womens Research Institute University of Pittsburgh, USA
Overview Rationale for rectal microbicide development Preclinical development of candidate rectal microbicides Evolving design of Phase 1 rectal safety studies Moving towards effectiveness studies
Rationale for Rectal Microbicide Development
Anal Intercourse in US Women (%) Lifetime experience of AI 40 30 20 10 0 Gross M et al. 2000 Civic D et al. 2000 Mosher WD et al. 2005 Erickson PI et al. 1995
Anal Intercourse in Women Outside the US 50 40 % 30 20 10 0 Brazil Peru South Africa Kenya Brazil: Guimares MD et al. 1995, South Africa: Karim SS and Ramjee G 1998 Peru: Caceres C et al. 1997, Kenya: Schwandt M et al. 2006
HIV Incidence in US MSM 15 10 5 Incidence (%) 0 Overall White Mixed Race Black Racial Group Sifakis F et al. JAIDS 2007
HIV Prevalence in African MSM 25 20 15 10 5 Prevalence (%) 0 Malawi Namibia Botswana Combined Baral et al. PLoS One 2009
Demographic Profile Mean age: 24.9 years Gay / homosexual: 49.5% Bisexual: 38.1% Found partner on the internet: 44.7% < 1:20 practiced safe sex Human rights abuse: 42.1% Baral et al. PLoS One 2009
Effect of RAI in Microbicide Trials Transmission Probability 1X 10X 20X
RAI in HPTN-059 Coitally Dependent Daily Use Tenofovir Placebo Tenofovir Placebo N=50 N=51 N=49 N=50 Ever anal sex 24% 25% 33% 28% Anal sex, (past 7 days) 2% 0% 4% 2%
RAI in HPTN-035 Baseline Characteristics Ever had anal sex BufferGel PRO2000 Placebo No Gel 4% 4% 5% 5%
ACASI HPTN-035B 6 4 2 0 0.2% 4.8% FTFI % Women Reporting Anal Sex
Preclinical Development of Candidate Rectal Microbicides
Rectosigmoid Anatomy
Effect of Osmolality on Mucosal Integrity Iso-osmolar Hyperosmolar Fuchs et al J Infect Dis 2007
Lubricants Vary in Osmolality Product Osmolality (Median mosm/kg) Tap water 3 Femglide 42 Semen 340 Gynol II 1182 Fleet enema 2127 KY Jelly 2424 Astroglide 3126 Prepair 4026 Fuchs et al J Infect Dis 2007
Colorectal Intestinal Explants Endoscopic biopsies + Absorbable gelatin sponge Abner SR et al. JID 2005, Fletcher P et al. AIDS 2006
Toxicity of Topical Microbicides in Colorectal Explants 100 80 60 40 20 0 CAP Methyl Cellulose N9 KY PRO 2000 4% PRO 2000 0.5% PRO 2000p SPL7013 SPL7013p UC781 1% UC781 0.1% UC781p Vena Gel % Viability Dezzutti C et al., AAC 2004
Tenofovir Explant Data 7000 6000 HIV-1 LAV and PMPA p-24 (pg/ml) 5000 4000 3000 2000 1000 783 MED/LAV PLAC/LAV PMPA/LAV 0 D1 D4 D7 D11 D14
Rectal Model Development Macaca nemestrina
Rectal Lavage Assay Lavage fluid Day 4 Combo Animal Day 4, T0 24 hrs post 3rd application Day 4, T30 post 4th application 7X 7X 15X 30X *Microbicides 2008 Poster #TA-057
Evolving Design of Phase 1 Rectal Safety Studies
Tabet et al. Open label frequency escalation safety study of 3.5% nonoxynol-9 gel versus replens Population monogamous couples 25 HIV negative MSM 10 HIV positive MSM Gel BID + RAI 3 times per week for 6 weeks 68 (97%) participants completed study Minor anoscopic or histological findings common Tabet et al. STD 1999
Phillips et al. 2% Nonoxynol-9 18 participants - open label study Endpoint Histology Sampling Baseline + 15 minutes + 2 hours + 8 hours Phillips et al. Contraception 2004
Phillips et al. Baseline + 15 minutes + 15 minutes + 2 hours + 2 hours + 8 hours Phillips et al. Contraception 2004
HPTN 056 Study Design Week -2 0 + 2 + 4 Screening Baseline Week 2 Week 4 Consent Physical Anoscopy Rectal GC/CH HIV Ab CD4 / Viral load Sigmoidoscopy Intestinal biopsy at 10cm and 30cm Cell isolation and flow cytometry Tissue cytokines Rectal immunoglobulins Tissue / rectal secretion viral load McGowan et al. JAIDS 2007
UC-781 Trial Design 0.1% Baseline Screening Enrollment Randomization Endoscopy 0.25% Placebo Single dose 2 nd Endoscopy 7 single Doses 3 rd Endoscopy Anton et al. CROI 2009
Explant Data HEC Placebo UC781 0.10% UC781 0.25% 10cm Cumulative P-24 at Day 14 (pg/ml) 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 V2 Visit V3 Cumulative P-24 at Day 14 (pg/ml) 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 V2 Visit V3 Cumulative P-24 at Day 14 (pg/ml) 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 V2 Visit V3 30cm Cumulative P-24 at Day 14 (pg/ml) 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 V2 Visit V3 Cumulative P-24 at Day 14 (pg/ml) 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 V2 Visit V3 Cumulative P-24 at Day 14 (pg/ml) 22000 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 V2 Visit V3 (HIV-1 BaL TCID 50 10 4 )
Future Phase 1 Rectal Microbicide Safety Studies Product Status Timeline Sponsor UC-781 Completed NIAID/DAIDS MTN-007 Planned Q2 2009 NIAID/DAIDS RMP-02 Planned Q2 2009 NIAID/DAIDS VivaGel Planned Q4 2009 NIAID/DMID PRO-2000 Planned Q4 2009 MDP MRC-UK UC-781 (RF) Possible Q4 2010 TBD
RMP-02 / MTN-006
RMP-02 / MTN-006 A Phase 1 rectal microbicide safety and acceptability trial of topically applied tenofovir compared with tablet Study population 18 sexually abstinent HIV negative men and women Study products Oral Tenofovir Topical 1% vaginal formulation of tenofovir Hydroxyethyl cellulose (HEC) placebo gel
RMP-02 / MTN-006 Single oral dose of tenofovir Single rectal dose of tenofovir 7 daily doses of tenofovir Pharmacokinetics Plasma PBMC Rectal fluid Tissue MMC Safety General Mucosal Explant Infection
RMP-02 / MTN-006 David Geffen School of Medicine at UCLA IOR: Peter Anton MD Pittsburgh, PA IOR: Ian McGowan MD PhD
MTN-007
MTN-007 Phase 1 randomized, double-blinded, placebo-controlled rectal safety and acceptability study of tenofovir 1% gel Approximately 60 sexually (RAI) abstinent, HIV-negative adults men and women Four study arms: 1% vaginal formulation of tenofovir Hydroxyethyl cellulose (HEC) placebo gel 2% nonoxynol-9 (Ortho-Gynol II) No product arm
MTN-007 Design 2% N-9 (N=15) 7-14 day interval 7-14 day interval N=60 1% Tenofovir (N=15) Baseline Evaluation Single dose 7 day daily doses HEC (N=15) Screening No Treatment (N=15) Endoscopy Safety/behavioral assessment
Secondary Endpoints Mucosal safety parameters: Epithelial sloughing Intestinal histopathology Intestinal mucosal mononuclear cell phenotype Intestinal mucosal cytokine Intestinal mucosal gene expression arrays Cytokine profile in rectal secretions Fecal calprotectin Microflora
MTN-007 Study Sites Pittsburgh, PA IOR: Ross Cranston MD Birmingham, AL IOR: Craig Hoesley MD Boston, MA IOR: Ken Mayer MD
Why have an N-9 arm in MTN- 007? Assessment of mucosal injury requires the use of esoteric and expensive assays Preliminary data from a UC-781 Phase 1 rectal safety study have not demonstrated changes in these mucosal safety parameters Rectal exposure to N-9 results in mild and transient epithelial disruption Mice Macaques Humans
Is inclusion of an N-9 arm safe? Histological recovery occurs within 1-8 hours Mice Humans Macaques Tabet et al. demonstrated minimal histological inflammation after up to 6 weeks treatment with a 3.5% formulation of N-9 All participants in MTN-007 will be sexually abstinent
Moving Towards Effectiveness Studies
For this reason, NIAID places a priority on developing HIV prevention tools that women can implement independently. One such method under study is a microbicide a gel, cream or foam intended to prevent the sexual transmission of HIV when applied topically inside the vagina or rectum. Statement of Anthony S. Fauci, M.D. Director, National Institute of Allergy and Infectious Diseases National Institutes of Health on National Women and Girls HIV/AIDS Awareness Day March 10, 2009
Next Steps Identify relevant population Develop rectal specific products Design rectal specific applicator Expanded safety study Effectiveness study
Populations for RM studies Phase 2 studies RAI sexually active men and women Higher risk populations Phase 2B studies 3% seroincidence MSM populations North America Latin America Africa
Microbicide Safety and Acceptability in Young Men NICHD R01 McGowan / Carballo-Dieguez Pittsburgh, Boston, Puerto Rico Phase 1 safety and acceptability of VivaGel Ethnically diverse MSM (18-30) Consensual RAI in last month Unprotected RAI in last year
Microbicide Safety and Acceptability in Young Men Stage 1A Screening 240 MSM Consensual RAI in last month URAI in last year Stage 1B 3 month Acceptability & Adherence study with placebo gel 120 MSM RAI in last 3 months STI negative Stage 2 Phase 1 VivaGel rectal safety study 42 MSM 80% adherence in Stage 1B McGowan & Carballo-Dieguez 2009
Rectal Specific Products CHARM Program Combination HIV Antiretroviral Microbicide Program DAIDS IPCP Program PI: Ian McGowan MD PhD Consortium University of Pittsburgh UCLA Johns Hopkins CONRAD
Rectal Specific Applicators Incorporates Fleet tip Can be operated with one hand Has grips for the fingers Can deliver a precise dose up to 10 ml Used across clinical trials, this MDD will reduce sources of acceptability and adherence variability Can be manufactured in gray color
Phase 2 Expanded Rectal Safety Study Double blind placebo controlled Population: 300 RAI sexually active men and women with 6 month follow-up Three study arms: Oral tenofovir + placebo tenofovir gel Placebo oral tenofovir + tenofovir gel Oral tenofovir + tenofovir gel Study endpoints Safety PK substudy Explant efficacy substudy
Phase 2B Rectal Safety and Effectiveness Study
Placebo Study Study Arms Oral tenofovir + Placebo gel Oral placebo + Tenofovir gel Oral tenofovir + Tenofovir gel Oral placebo + Placebo gel Seroincidence 4% Power 90% Endpoints per pair wise comparison / total Person years per endpoint 90-100 2 pair wise comparisons Total: 180-200 40-50 Follow-up 2 years Sample size 3,500 5,000
Placebo Study Active Comparator Study Study Arms Oral tenofovir + Placebo gel Oral tenofovir Oral placebo + Tenofovir gel Oral tenofovir + Tenofovir gel Oral placebo + Placebo gel Oral tenofovir + Tenofovir gel Seroincidence 4% 4% Power 90% 90% Endpoints per pair wise comparison / total 90-100 2 pair wise comparisons Total: 180-200 88 1 pair wise comparison Total: 88 Person years per endpoint 40-50 120 Follow-up 2 years 2 years Sample size 3,500 5,000 5,000
Summary There is a clear rationale for the development of rectal microbicides The design of rectal safety studies now includes immunotoxicity assays Rectal specific products and applicators are being developed It is time to move to the Phase 2 and beyond
IAS Meeting, Cape Town, South Africa, July 2009 Rectal Microbicide Development, An African Perspective Ian McGowan MD PhD Chris Beyrer MD James McIntyre MD Jim Pickett Sponsored by AVAC, IRMA, MTN
Acknowledgements MTN is funded by NIAID (5U01AI068633-03), NICHD and NIMH, all of the U.S. National Institutes of Health.